ABSTRACT

(+/-)-Tramadol is a synthetic analogue of codeine. It is
a central analgesic with a low affinity for opioid receptors. Its selectivity
for mu receptors has recently been demonstrated, and the M1 metabolite of
tramadol, produced by liver O-demethylation, shows a higher affinity for opioid
receptors than the parent drug. The rate of production of this M1 derivative
(O-demethyl tramadol), is influenced by a polymorphic isoenzyme of the
debrisoquine-type, cytochrome P450 2D6 (CYP2D6). Nevertheless, this affinity for
mu receptors of the CNS remains low, being 6000 times lower than that of
morphine. Moreover, and in contrast to other opioids, the analgesic action of
tramadol is only partially inhibited by the opioid antagonist naloxone, which
suggests the existence of another mechanism of action. This was demonstrated by
the discovery of a monoaminergic activity that inhibits noradrenaline
(norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake, making a
significant contribution to the analgesic action by blocking nociceptive
impulses at the spinal level. (+/-)-Tramadol is a racemic mixture of 2
enantiomers, each one displaying differing affinities for various receptors.
(+/-)-Tramadol is a selective agonist of mu receptors and preferentially
inhibits serotonin reuptake, whereas (-)-tramadol mainly inhibits noradrenaline
reuptake. The action of these 2 enantiomers is both complementary and
synergistic and results in the analgesic effect of (+/-)-tramadol. After oral
administration, tramadol demonstrates 68% bioavailability, with peak serum
concentrations reached within 2 hours. The elimination kinetics can be described
as 2-compartmental, with a half-life of 5.1 hours for tramadol and 9 hours for
the M1 derivative after a single oral dose of 100mg. This explains the
approximately 2-fold accumulation of the parent drug and its M1 derivative that
is observed during multiple dose treatment with tramadol. The recommended daily
dose of tramadol is between 50 and 100mg every 4 to 6 hours, with a maximum dose
of 400 mg/day; the duration of the analgesic effect after a single oral dose of
tramadol 100mg is about 6 hours. Adverse effects, and nausea in particular, are
dose-dependent and therefore considerably more likely to appear if the loading
dose is high. The reduction of this dose during the first days of treatment is
an important factor in improving tolerability. Other adverse effects are
generally similar to those of opioids, although they are usually less severe,
and can include respiratory depression, dysphoria and constipation. Tramadol can
be administered concomitantly with other analgesics, particularly those with
peripheral action, while drugs that depress CNS function may enhance the
sedative effect of tramadol. Tramadol should not be administered to patients
receiving monoamine oxidase inhibitors, and administration with tricyclic
antidepressant drugs should also be avoided. Tramadol has pharmacodynamic and
pharmacokinetic properties that are highly unlikely to lead to dependence. This
was confirmed by various controlled studies and postmarketing surveillance
studies, which reported an extremely small number of patients developing
tolerance or instances of tramadol abuse. Tramadol is a central acting analgesic
which has been shown to be effective and well tolerated, and likely to be of
value for treating several pain conditions (step II of the World Health
Organization ladder) where treatment with strong opioids is not required.